Nevertheless, epidemiologists (and folks in health promotion) appear to like the notion that there is such a weight (at least at the population level), and often define it as the weight (or rather BMI level) where people have the longest life-expectancy.
Readers of this literature may have noticed that the BMI level associated with the lowest mortality has been creeping up.
Case in point, a new study by Shoaib Afzal and colleagues from Denmark, published in JAMA, that looks at the relationship between BMI and mortality in three distinct populations based cohorts.
The cohorts are from the same general population enrolled at different times: the Copenhagen City Heart Study in 1976-1978 (n = 13 704) and 1991-1994 (n = 9482) and the Copenhagen General Population Study in 2003-2013 (n = 97 362). All participants were followed up to November 2014, emigration, or death, whichever came first.
The key finding of this study is that over the various studies, there was a 3.3 unit increase in BMI associated with the lowest mortality when comparing the 1976-1978 cohort with that recruited in 2003-2013.
Thus, The BMI value that was associated with the lowest all-cause mortality was 23.7 in the 1976-1978 cohort, 24.6 in the 1991-1994 cohort, and 27.0 in the 2003-2013 cohort.
Similarly, the corresponding BMI estimates for cardiovascular mortality were 23.2, 24.0, and 26.4, respectively, and for other mortality, 24.1, 26.8, and 27.8, respectively.
At a population level, these shifts are anything but spectacular!
After all, a 3.3 unit increase in BMI for someone who is 5’7″ (1.7 m) is just over 20 lbs (~10 Kg).
In plain language, this means that to have the same life expectancy today, of someone back in the late 70s, you’d actually have to be about 20 lbs heavier.
While I am sure that these data will be welcomed by those who would argue that the whole obesity epidemic thing is overrated, I think that the data are indeed interesting for another reason.
Namely, they should prompt speculation about why heavier people are living longer today than before.
There are two general possible explanations for this:
For one these changes may be the result of a general improvement in health status of Danes related to decreased smoking, increased physical activity or changes in social determinants of health (e.g. work hours).
On the other hand, as the authors argue, this secular trend may be that improved treatment for cardiovascular risk factors or complicating diseases, which has indeed reduced mortality in all weight classes, may have had even greater beneficial effects in people with a higher BMI. Thus, obese individuals may have had a higher selective decrease in mortality.
There is in fact no doubt that medical management of problems directly linked to obesity including diabetes, hypertension and dyslipidemia have dramatically improved over the past decades.
Thus, it appears that the notion of “healthy” weight is a shifting target and that changes in lifestyle and medical management may have more than compensated for an almost 20 lb weight increase in the population.
This is all the more reason that the current BMI cutoffs and weight-centric management of obesity both at a population and individual level may need to be revisited or at least tempered with measures of health that go beyond just numbers on the scale.
While this approach can be highly effective, it does require training, resources and ongoing (lifelong?) interventions (not unlike most other chronic diseases).
Now a rather comprehensive paper by Soleyman and colleagues from the University of Birmingham, Alabama, published in Obesity Reviews provides an overview of obesity management in primary care.
As readers are well aware, our body weight are tightly regulated by a complex neuroendocrine system and defends us agains weight loss through a multi-faceted physiological response to prevent further weight loss and restore body weight.
As the authors note,
“To maintain weightloss, individuals must adhere to behaviours that oppose these physiological adaptations and the other factorsfavouring weight regain. However, it is difﬁcult for peoplewith obesity to overcome physiology with behaviour over the long term. Common reasons for weight regain include decreased caloric expenditure, decreased self-weighing frequency, increased caloric intake, increased fat intake and eating disinhibition over time.”
The paper provides a succinct overview of the evidence supporting behavioural, medical and surgical obesity treatments.
It also reiterates the basic principles of obesity management as outlined in the various guidelines:
1. Obesity is a chronic disease that requires long-term management. It is important to approach patients with information regarding the health implications.
2. The goal of obesity treatment is to improve the health of the patient, and it is not intended for cosmetic purposes.
3. The cornerstone of therapy is comprehensive lifestyle intervention from informed PCPs or other healthcare professionals.
4. The initial goal of therapy is a weight loss of 5–10% in most patients, as this is sufﬁcient to ameliorate many weight-related complications. However, weight loss of ≥10% may be needed to improve certain weight-related complications, such as obstructive sleep apnoea.
5. Consideration should be given to the use of a weight-loss medication or possible bariatric surgery, as the addition of these treatment modalities to lifestyle therapy can promote greater weight loss and maintain the weight loss for a longer period of time.
6. It is important for clinicians to evaluate the patient for weight-related complications, that can be improved by weight loss, and to consider such patients for more aggressive treatment.
As for how to get more primary care clinics to actually implement these approaches, the authors note that,
“Primary care practitioners need to address the problem of obesity in their patients, just as they would with any other chronic condition such as hypertension or type 2 diabetes, and to ensure that their patients are aware of the health risks of obesity.”
Again something that the Canadian Obesity Network is working hard to promote in this country.
Earlier this week, Novo Nordisk, the maker of Victoza and Saxenda, announced top-line results from the LEADER trial, which investigated the cardiovascular safety of liraglutide 1.8mg over a period of up to 5 years in more than 9,000 adults with type 2 diabetes at high risk of major adverse cardiovascular events.
The trial compared the addition of either liraglutide 1.8 mg or placebo to standard care and apparently met the primary endpoint of showing non-inferiority as well as demonstrating superiority, with a significant reduction in cardiovascular risk.
According to the news release, liraglutide demonstrated superior reduction of major adverse cardiovascular events in the primary endpoint of the study (composite outcome of the first occurrence of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke), a reduction that that was derived from all three components of the endpoint.
The safety profile of liraglutide in LEADER was reported as, “generally consistent with previous liraglutide clinical studies”.
While it is hard to fully interpret the study, the detailed results of which will be reported at the American Diabetes Conference in a few months, this may well be a landmark trial both for diabetes but also for obesity medications.
Thus, although LEADER did not test the higher liraglutide 3 mg dose indicated for obesity, it is indeed reassuring that at least the liraglutide 1.8 mg dose indicated for diabetes, did not increase (and even decreased) the risk for cardiovascular complications.
This is of importance, as readers may be well aware that the history of anti-obesity medications is plagued with drugs that raised safety concerns regarding cardiovascular events.
Thus, while we await the full results of the LEADER trial, there appears hope for optimism that with liraglutide we may finally have a drug for the treatment of obesity that has a favourable cardiovascular safety profile.
That would be a landmark indeed.
Disclaimer: I have received honoraria as a consultant and speaker for Novo Nordisk
Yesterday, Zafgen released data from its phase 2b trial of beloranib in patients with severe obesity complicated by type 2 diabetes.
Zafgen recently announced that its phase 2b trial (ZAF-203) of the MetAP2 inhibitor beloranib in 152 patients with severe obesity complicated by type 2 diabetes.
Accompanying an impressive 12.7 and 13.5% weight loss on 1.8 mg and 1.2 mg beloranib (vs 3.1% for placebo), respectively.
Unfortunately, these results are marred by the ongoing concern over potential thrombogenic adverse effects.
Thus of the nine serious adverse events identified in eight patients during the trial, one was a pulmonary embolism in the 1.2 mg treatment group. A subsequent screening process (following the FDA’s partial clinical hold on the trial) identified silent pulmonay emboli in two additional patients in the beloranib treatment arms.
Currently Zafgen is working to better understand the potential mechanisms underlying the apparent thrombogenic risk as well as developing a risk-mitigation strategy (at least for studies in patients with Prader-Willi Syndrome) that would help resolve the complete clinical hold the FDA placed on the beloranib for now.
Thus, the future remains uncertain for what would otherwise certainly be a big step forward to fill the continuing gap of more effective medical treatments for obesity.
Disclaimer: I have received consulting honoraria from Zafgen, the makers of belanorib
Now a paper by Argyro Syngelaki and colleagues from the UK, published in the New England Journal of Medicine, suggests that the anti-diabetes drug metformin may limit weight gain in pregnant non-diabetic women with obesity and also reduce the incidence of pre-eclampsia.
The researchers randomised 450 pregnant women with a BMI greater than 35 and no diabetes to either metformin (3 g/day) or placebo from weeks 12-18 weeks of gestation till delivery in a double-blind fashion.
Among the 400 women who completed the study, those on metformin gained about 2 Kg less weight than the placebo group.
There was also an almost 75% decrease in the risk of developing preeclampsia.
Despite these effects, metformin did not significantly reduce the incidence of large-for-gestational-age babies or other adverse neonatal outcomes.
While these findings may be somewhat disappointing with regard to outcomes in the offspring, the reduction in pre-eclampsia is impressive and, if confirmed, could well be an interesting use of this compound in high-risk pregnancies.